The overall objectives of this project are concerned with the understanding of the relationship between structure, biological activity, immunoreactivity and metabolic function of insulin in pursuit of the elucidation of the mechanism of action of this hormone. Within this general framework we are pursuing (1) the synthesis of a wide spectrum of insulin analogs, their biological and immunochemical evaluation and their binding ability to the membranes of the cells of target organs, (2) correlation of changes in structure on the conformation and on the metabolic effects of insulin, and (3) synthesis of isotopically labeled biologically active insulin and its use in the study of the metabolic fate of this hormone.